We propose to continue multidisciplinary studies of the role of human papillomaviruses (HPV) in the etiology of anogenital cancers. The nucleus of this effort is a series of case-control studies which address the risk- factors involved in squamous cell cervical cancer, anal cancer, vulvar cancer, vaginal cancer adenocarcinoma of the cervix and penile cancer. Eligible subjects will be those diagnosed with one of these cancers between July 1994 through June 1998 together with appropriate controls. Results from these studies will add to the data base accumulated over the previous 8 years of this Program Project. In the previous years of this program the main focus has been on HPV and although that focus will be continued we now place equal stress on other factors involved in the etiology of these cancers. Tissue specimens will be tested for HPV and biological markers affecting proliferation, prognosis and host susceptibility. Blood samples will be collected for HPV serology and for evidence of HSV-2 infection. Development of serological tests for HPV has been one of the major accomplishments of this program and these will be used to identify serological markers for HPV infection and tumor progression or inhibition. These studies also form the basis for developing an understanding of the immune response to HPV and the design of therapeutic strategies. The cell-mediated response to HPV infection will be investigated as will the potential role of HLA genotype. As with most other cancers, anogenital cancer has the characteristics of a multistep process to malignancy. The steps in this process will be investigated in an effort to identify chromosomal regions in anogenital cancers subject to non-random deletion, rearrangement or amplification. These indicators of genetic instability will be analyzed for evidence of oncogenes and tumor suppressor genes mapping in regions of chromosomal abnormality. An extension of the case-control studies supported by this Program Project into an evaluation of prognostic markers is timely, since improvement in prognosis has not been evident in women diagnosed with cervical cancer despite a decrease in mortality from this disease. An analysis of tumor markers, as shown above, and HPV presence will be conducted on tissue specimens from women diagnosed with anogenital cancer between 1986 and 1996, in order to develop data which could be used to define therapies.